Postsynaptic Striatal Dopamine Research Articles

Tardive Dyskinesia: Assessing and Treating a Debilitating Side Effect of Prolonged Antipsychotic Exposure

Tardive Dyskinesia: Assessing and Treating a Debilitating Side Effect of Prolonged Antipsychotic Exposure

Anti-dyskinetic effect of anpirtoline in animal models of L-DOPA-induced dyskinesia

The serotonin system has emerged as a potential target for anti-dyskinetic therapy in Parkinson's disease. In fact, serotonin neurons can convert L-DOPA into dopamine, and mediate its synaptic release. However, they lack a feedback control mechanism able to regulate synaptic dopamine levels, which leads to un-physiological stimulation of post-synaptic striatal dopamine receptors. Accordingly, drugs able to dampen the activity of serotonin neurons can suppress L-DOPA-induced dyskinesia in animal models of Parkinson's disease.Here, we investigated the ability of the 5-HT1A/1B receptor agonist anpirtoline to counteract L-DOPA-induced dyskinesia in L-DOPA-primed 6-OHDA-lesioned rats and MPTP-treated macaques. Results suggest that anpirtoline dose-dependently reduced dyskinesia both in rats and monkeys; however, the effect in MPTP-treated macaques was accompanied by a worsening of the Parkinson's disease score at significantly effective doses (1.5 and 2.0mg/kg). At a lower dose (0.75mg/kg), anpirtoline markedly reduced dyskinesia in 4 out of 5 subjects, but statistical significance was prevented by the presence of a non-responsive subject.These results provide further evidence that the serotonin neurons contribute both to the pro-dyskinetic effect of L-DOPA and to its therapeutic efficacy in the rat and monkey models of Parkinson's disease.

Time course of changes in rotational behavior and DA metabolism in rats lesioned unilaterally with the selective proteasome inhibitor lactacystin

A growing body of evidence suggests that proteasomal dysfunction may play an important role in the pathogenesis of PD. The aim of our study was to examine the effect of unilateral administration of lactacystin, a selective proteasome inhibitor, on rotational behavior and striatal and nigral metabolism of dopamine (DA). Male Wistar rats were used for the study. The animals were injected unilaterally with a single dose of lactacystin (2.5 μg/2 μl) into the substantia nigra (SN) pars compacta. After injection, the rats were examined for spontaneous and apomorphine (0.25 mg/kg)induced rotational behavior in rotameter bowls throughout 60 min. All the testing was done on days 1, 4, 7, 14 and 21 after lactacystin administration. The animals were killed by decapitation on post-lesional days 1, 4, 7 and 21. The levels of DA and its metabolites were assayed in striatal and nigral homogenates using an HPLC method. Behavioral studies showed that the lactacystin-lesioned rats, but not the shamoperated animals, displayed a strong spontaneous circling behavior contralateral to the lesioned side on the 1 and 4 day after lactacystin treatment. This effect disappeared 1 week after the lesion. After apomorfine treatment on day 7, 14 and 21 days after surgery, no contralateral turning was observed in the lesioned rats. Biochemical studies demonstrated that lactacystin evoked a progressive loss in DA and its metabolites in the ipsilateral striatum and SN compared to the ipsilateral striatum of the sham-operated rats. The decreases started on the 7 day after lesion except for the drop in the nigral DA level which began already on the 4 day after surgery. After 21 days, the decline in DA level exceed 90% both in the striatum and SN. As regards DA catabolism, lactacystin evoked a progressive acceleration of MAO-dependent oxidative DA catabolism (DOPAC/DA), COMT-dependent Omethylation (3-MT/DA) and total DA catabolism (HVA/DA), both in the ipsilateral striatum and SN. The present study shows that lactacystin produces biochemical changes characteristic of degeneration of the DA system, namely a robust progressive decrease in DA level and an increase in DA catabolism. However, the presence of spontaneous contralateral rotations on the first few days after lesion indicates that other, probably non-DA mechanisms may play a role in this phenomenon. On the other hand, the lack of contralateral rotations after apomorphine up to three weeks after surgery suggests that the lactacystin-induced dramatic loss of striatal DA does not lead to supersensitivity of the striatal postsynaptic DA receptors.

Entacapone

Importance of the field: Levodopa (LD) is an efficient drug for patients with Parkinson's disease (PD). Its short half-life supports peaks and troughs. These plasma fluctuations support alternating stimulation of striatal postsynaptic dopamine receptors and thus onset of motor complications. They are significant components for the quality of treatment of PD patients.Areas covered in this review: This review discusses peripheral components of motor complication manifestation related to LD metabolism.What the reader will gain: LD troughs are associated with wearing off, which is reappearance of motor symptoms with decreasing drug effect. The addition of the catechol-O-methyltransferase inhibitor entacapone (EN) to LD/carbidopa (CD) improves wearing off, as EN prolongs LD half-life and avoids troughs. LD peaks are mostly related to peak dose dyskinesia, which are involuntary movements due to a central overstimulation with dopamine. One time addition of EN to LD/CD showed no increase of maximum LD concentration, but repeat EN supplementation to LD/CD elevated LD bioavailability and peaks.Take home message: These pharmacokinetic data may explain the failure of the STRIDE-PD study, which aimed to show a delayed interval of dyskinesia onset with LD/CD/EN therapy. This study only allowed up titration with a fixed LD intake every 4 h. But dyskinesia occurrence may require down titration of LD dose or delay of next LD intake.

Clozapine prolongs hypotonic immobility in rats with bilateral 6-hydroxydopamine lesions of the striatum

Clozapine does not induce classical catalepsy. One explanation is that endogenous dopamine (DA) readily displaces clozapine from postsynaptic striatal DA receptors. If the latter were true, then depletion of striatal DA should permit clozapine to induce classical catalepsy. Rats received bilateral sham or 6-hydroxydopamine (6-OHDA) lesions of the striatum. Catalepsy using the bar test was assessed on days 21, 28 and 35 after i.p. vehicle, haloperidol (0.75 mg/kg) or clozapine (20 mg/kg). Brains were harvested on day 36 and striatal DA was assayed. A 97% depletion of striatal DA was associated with a significant increase in the duration of immobility after haloperidol or clozapine administration. Both in sham as well as in 6-OHDA lesioned animals, however, the duration of immobility was greater after haloperidol than after clozapine. Furthermore, clozapine-treated animals were hypotonic and did not show the classic rigidity of haloperidol catalepsy. While clozapine's low propensity to induce immobility in animals and extrapyramidal symptoms in man may depend in part on endogenous striatal DA, other mechanisms must also be involved.

Clozapine prolongs hypotonic immobility in rats with bilateral 6-hydroxydopamine lesions of the striatum

Clozapine does not induce classical catalepsy. One explanation is that endogenous dopamine (DA) readily displaces clozapine from postsynaptic striatal DA receptors. If the latter were true, then depletion of striatal DA should permit clozapine to induce classical catalepsy. Rats received bilateral sham or 6-hydroxydopamine (6-OHDA) lesions of the striatum. Catalepsy using the bar test was assessed on days 21, 28 and 35 after i.p. vehicle, haloperidol (0.75 mg/kg) or clozapine (20 mg/kg). Brains were harvested on day 36 and striatal DA was assayed. A 97% depletion of striatal DA was associated with a significant increase in the duration of immobility after haloperidol or clozapine administration. Both in sham as well as in 6-OHDA lesioned animals, however, the duration of immobility was greater after haloperidol than after clozapine. Furthermore, clozapine-treated animals were hypotonic and did not show the classic rigidity of haloperidol catalepsy. While clozapine's low propensity to induce immobility in animals and extrapyramidal symptoms in man may depend in part on endogenous striatal DA, other mechanisms must also be involved.

Pharmacological involvement of the calcium channel blocker flunarizine in dopamine transmission at the striatum

Single intrastriatal microinjections of 25, 50 and 100 nmol/μl of flunarizine in normal rats produced a dose-dependent turning behavior toward the injected side when they were challenged with apomorphine (1 mg/kg, s.c). This effect was seen at 1, 3 and 7 days following administration of the high dose of flunarizine, but had subsided by 24 h after administration of the intermediate dose; the low dose was ineffective. However, intrastriatal injection of the high dose of flunarizine resulted in a local lesion and thereafter this dose was not used. A similar dose-response relationship was determined for nifedipine, an L-type calcium channel antagonist. Injection of this antagonist did not result in apomorphine-elicited rotational behavior, reflecting its lack of antidopaminergic action. Intrastriatal injections of haloperidol (5 μg/μl), an antagonist of dopamine D 2 receptors, or the sodium channel blocker lidocaine (40 μg/μl), were given in order to compare their effects to those observed with flunarizine. Intracerebral injection of haloperidol produced ipsilateral turning in response to systemic administration of apomorphine given 60 min after. The same response was obtained with the injection of apomorphine 10 min after the injection of intracerebral lidocaine. This effect was no longer apparent 24 h after the microinjection of haloperidol and 60 min after the injection of lidocaine. In rats rendered hemiparkinsionian by lesioning the nigrostriatal pathway with 6OHDA, intrastriatal microinjection of flunarizine (50 nmol/μl) significantly reduced apomorphine (0.2 mg/kg, s.c.)-elicited turning behavior towards the non-lesioned side. These results suggest an antidopaminergic effect of flunarizine mediated by antagonistic action of post-synaptic striatal dopamine receptors. However, an action of the drug on sodium channels may not be ruled out. These studies offer additional supporting evidence for the induction or aggravation of extrapyramidal side-effects in patients receiving flunarizine.

Modulation of pre- and postsynaptic dopamine D2 receptor function by the selective kappa-opioid receptor agonist U69593.

The repeated administration of selective kappa-opioid receptor agonists prevents the locomotor activation produced by acute cocaine administration and the development of cocaine-induced behavioral sensitization. Previous studies have shown that dopamine (DA) D2 autoreceptors modulate the synthesis and release of DA in the striatum. Evidence that kappa agonist treatment downregulates DA D2 receptors in this same brain region has recently been obtained. Accordingly, the present studies were undertaken to examine the influence of repeated kappa-opioid receptor agonist administration on pre- and postsynaptic DA D2 receptor function in the dorsal striatum using pre- and postsynaptic receptor-selective doses of quinpirole. Rats were injected once daily with the selective kappa-opioid receptor agonist U69593 (0.16-0.32 mg/kg s.c.) or vehicle for 3 days. Microdialysis studies assessing basal and quinpirole-evoked (0.05 mg/kg s.c.) DA levels were conducted 2 days later. Basal and quinpirole-stimulated locomotor activity were assessed in a parallel group of animals. The no-net flux method of quantitative microdialysis revealed no effect of U69593 on basal DA dynamics, in that extracellular DA concentration and extraction fraction did not differ in control and U69593-treated animals. Acute administration of quinpirole significantly decreased striatal DA levels in control animals, but in animals treated with U69593, the inhibitory effects of quinpirole were significantly reduced. Quinpirole produced a dose-related increase in locomotor activity in control animals, and this effect was significantly attenuated in U69593-treated animals. These data reveal that prior repeated administration of a selective kappa-opioid receptor agonist attenuates quinpirole-induced alterations in DA neurotransmission and locomotor activity. These results suggest that both pre- and postsynaptic striatal DA D2 receptors may be downregulated following repeated kappa-opioid receptor agonist administration. Synapse 39:343-350, 2001. Published 2001 Wiley-Liss, Inc.

Reduced striatal dopamine receptors in Alzheimer's disease

Many patients with Alzheimer's disease (AD) develop parkinsonian symptoms, suggesting an overlapping between AD and Parkinson's disease (PD). However, pathologic and neurochemical studies indicate that the involvement of the dopamine system may be different in the two conditions. Using single photon emission tomography, we determined the relative specific striatal uptake (striatum to cerebellum ratio) of the D2 receptor ligand [123I]-IBZM in 15 AD patients without overt extrapyramidal symptoms (three subjects presented mild rigidity and bradykinesia) and nine age-matched controls. Mean specific activity in striatal regions of AD patients (1.35 +/- 0.09) was significantly reduced from control mean (1.59 +/- 0.03). Because such changes were evident even in the absence of overt parkinsonian symptomatology, our data indicate that alterations of striatal D2 receptors may be part of the pathologic abnormalities of AD. In addition, the mechanisms underlying extrapyramidal symptoms in AD (decline of postsynaptic striatal dopamine receptors) appear different from the prevalent presynaptic nigrostriatal alterations typical of PD.

Adrenal medulla grafts in the hemiparkinsonian rat: profile of behavioral recovery predicts restoration of the symmetry between the two striata in measures of pre- and postsynaptic dopamine function

Following unilateral striatal dopamine depletion, the hemiparkinsonian rat exhibits rotational behavior in response to amphetamine and apomorphine. The rotational behaviors induced by these drugs are thought to reflect an asymmetry in presynaptic striatal dopamine release and an asymmetry in postsynaptic striatal dopamine receptor function, respectively. Grafts of adrenal medulla cells in the lateral ventricle of hemiparkinsonian rats have been reported to reduce behavioral asymmetry. More than one profile of behavioral recovery, however, is observed. Some animals show a graft-induced decrease only in the response to apomorphine, but others show a decrease in the response to amphetamine, and still others show a decrease in the behavioral responses to amphetamine and apomorphine. In this report, amphetamine- and apomorphine-induced turning behaviors were determined in hemiparkinsonian rats prior to and following intraventricular grafts of adrenal medulla or control tissue. Both bilateral intrastriatal microdialysis in freely moving animals and quantitative dopamine receptor autoradiography procedures were conducted in each animal so as to determine the relations between pre- and postsynaptic dopaminergic measures as well as the association between these measures and the different profiles of behavioral recovery after adrenal medulla grafts. We report here that in animals with an adrenal medulla graft-induced decrease in the behavioral response to amphetamine, the balance between the two striata in extracellular striatal dopamine concentrations and D2 dopamine receptor binding was restored. Furthermore, enhanced extracellular striatal dopamine concentrations were highly correlated with the graft-induced symmetry in striatal D2 dopamine receptor binding. In contrast to animals with decreased amphetamine-induced turning, in animals with a graft-induced decrease exclusively in response to apomorphine, the presynaptic symmetry was not restored and there was a significantly smaller effect on D2 receptor binding. We conclude that those animals that show decreased amphetamine-induced turning after adrenal medulla grafts had the most effective grafts, and suggest that methods designed to optimize this behavioral profile are most likely to lead to enhanced clinical efficacy with this procedure.

Decrease of D2 receptors indicated by 123I-iodobenzamide single-photon emission computed tomography relates to neurological deficit in treated Wilson's disease.

Single-photon emission computed tomography with 123I-iodobenzamide, a dopamine D2 receptor antagonist, was employed to study dopamine D2 receptor densities in 17 patients with biochemically proved Wilson's disease and stable neurological status with therapy and in 5 age-matched control subjects. Of the 17 patients with Wilson's disease, 5 were neurologically asymptomatic, 3 had cerebellar signs, 1 exhibited a mild parkinsonian syndrome, 7 showed a parkinsonian syndrome and cerebellar signs, and 1 had generalized dystonia and a parkinsonian syndrome. In 5 age-matched control subjects specific isotope binding as calculated by the basal ganglia to frontal cortex ratio was 1.57 +/- 0.04 (mean +/- standard deviation). The ratio in patients with Wilson's disease ranged from 1.56 +/- 0.05 (n = 5, asymptomatic patients) to 1.17 +/- 0.02 (n = 4, marked neurological impairment). We observed an almost linear correlation between the reduction of 123I-iodobenzamide (IBZM) binding and the severity of neurological signs at the time of IBZM-SPECT (correlation coefficient, -0.84; p < 0.01). We suggest that the reduction of postsynaptic striatal dopamine D2 receptors as detected by IBZM-SPECT reflects striatal neuronal damage in Wilson's disease.

Comparison of motor response to apomorphine and levodopa in Parkinson's disease.

The magnitude and pattern of motor responses to single doses of subcutaneous apomorphine and oral levodopa were compared in 14 patients with Parkinson's disease. Although apomorphine produced much shorter motor responses than levodopa, the quality of response to the two drugs was virtually indistinguishable. These clinical observations support the notion that integrity of striatal post-synaptic dopamine receptors is a key determinant of responsiveness to dopaminergic treatment in Parkinson's disease.

Activation of postsynaptic striatal dopamine receptors, monitored by efflux of cAMP in vivo

Intracerebral dialysis was used to monitor the change of extracellular concentration of striatal cAMP in rats anaesthetised with chloral hydrate. Forskolin (1–10 μM), an activator of adenylate cyclase, caused a concentration-dependent increase in efflux of cAMP, which was decreased by (+)PHNO (10 μM), an effect probably mediated by D 2 sites, since (−)-sulpiride, a D 2 receptor antagonist prevented these effects. Dopamine (1–100 μM) also increased the efflux of cAMP but only when the activity of monoamine oxidase and reuptake of dopamine were concomitantly blocked. The D 1 receptor agonist SKF 38393 (1–100 μM) caused a concentration-dependent increase in efflux of cAMP, which was blocked by the D 1 receptor antagonist SCH 23390 (1–100 μM), but was unaffected by the D 2 receptor antagonist sulpiride (10 μM) or by depletion of the concentration of striatal dopamine after pretreatment with 6-hydroxydopamine. Taken together, these results indicate that intracerebral dialysis may be used to monitor the interaction of drugs with post-synaptic dopamine receptors in vivo.

Cerebrospinal fluid homovanillic acid and parkinsonism in Huntington's disease.

In Huntington's disease (HD), normal or decreased levels of homovanillic acid (HVA) in cerebrospinal fluid (CSF) have been reported but have not been analyzed with respect to severity of parkinsonism, which in certain cases may be a predominant feature of the illness. We obtained CSF by lumbar puncture from four groups of nonmedicated subjects: (1) those with HD in the earliest stages of illness (n = 51), (2) those with parkinsonism, including idiopathic (n = 10) and atypical forms (n = 4), (3) those with nonparkinsonian movement disorders (n = 19), and (4) normal volunteers (n = 4). HVA was determined by high-pressure liquid chromatography with electrochemical detection, and motor signs were assessed in standardized fashion. The parkinsonian group had reduced levels of CSF HVA, but the other groups showed no significant differences. For those with HD, no correlation was found between HVA level and severity of parkinsonism, and there were no differences in HVA level between those subjects with (n = 14) or without (n = 37) prominent parkinsonism or between subjects whose age at illness onset was 30 years or less (n = 16) and those whose age at onset was over 30 (n = 35). Our findings indicate that in early, untreated HD, CSF HVA is in the normal range and does not correlate with the severity of parkinsonism. This observation supports neuropathological findings suggesting that parkinsonian features in HD are largely related to the loss of postsynaptic striatal dopamine receptors rather than to presynaptic nigral degeneration.

Conditional tolerance to haloperidol-induced catalepsy is not caused by striatal dopamine receptor supersensitivity.

The purpose of this study was to determine if non-pharmacological stimuli influence behavioural tolerance to haloperidol via striatal postsynaptic dopamine receptors. Rats received daily haloperidol and saline in two different environments for a period of 28 days. After this conditioning period half of the rats received haloperidol in the haloperidol-associated environment, whereas the other half received haloperidol in the saline-associated environment. All rats were tested for catalepsy and at the end of the last catalepsy test, striatal DOPAC, HVA and ACh were determined. Only the rats tested in the haloperidol-associated environment were behaviourally tolerant to haloperidol. In contrast, both groups were biochemically tolerant to haloperidol. These results indicate that environmental cue factors govern the development of behavioural tolerance to haloperidol, rather than biochemical factors (striatal DA super-sensitivity). In addition, these factors do not exert their influence on behavioural tolerance via striatal DA receptors.

The influence of estrogen on nigrostriatal dopamine activity: Behavioral and neurochemical evidence for both pre- and postsynaptic components

The results of 3 experiments examining the influence of estrogen on the nigrostriatal dopamine (DA) system are reported. In two experiments the influence of hormonal manipulations on amphetamine (AMPH)-induced rotational behavior was investigated using rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. It was found that: (1) female rats in estrus make more rotations than ovariectomized (OVX) rats; and (2) estrogen treatment (5 μg estradiol benzoate, daily for 4 days) in OVX rats enhances AMPH-induced rotational behavior 4 h and 4 days after estrogen treatment. During the intervening period, at 24 h after cessation of estrogen treatment, control and hormone-treated animals did not differ. In a third experiment, the effect of estrogen treatment on the release of endogenous DA from striatal tissue slices in superfusion was examined. Estrogen enhanced AMPH-stimulated striatal DA release 4 h after the last treatment relative to OVX controls. However, 24 h and 4 days after estrogen treatment DA release had returned to control levels. It is suggested that estrogen has an immediate potentiating effect on striatal DA release, and this may be responsible for the increased behavioral response to AMPH 4 h after estrogen treatment. The previously demonstrated increase in postsynaptic striatal DA receptors may be responsible for the second increase in AMPH-induced rotational behavior, that occurs 4 days after estrogen treatment.

Tardive dyskinesia: I. Physiopathology and treatment

The major breakthrough in the treatment of mental diseases was the introduction of neuroleptics in the early 50's. Soon after this an increasing number of patients under the use of these drugs presented involuntary abnormal orofacial movements which have been considered directly dependent on the drug action. The term "tardive dyskinesia" (TD) was coined for these movements. Many theories have been put forward to explain the pathophysiology of TD. The most prominent theory concerns with the possibility of denervation hypersensitivity occurring in striatal post-synaptic dopamine neurons. The authors review the most important theories and offer a new possibility based on the assumption that the post-synaptic dopamine receptors under chronic neuroleptic action develop a shift in its affinity towards the direction of agonist action. This means that the post-synaptic receptor increase its affinity, and possibly its number, to agonist drugs and dopamine. The paper includes a review of the main drugs used in this condition, attempting to explain the specific sites where they act, either in the dopaminergic, cholinergic or GABA--ergic systems.

Effect of dopamine system activation on substantia nigra pars reticulata output neurons: variable single-unit responses in normal rats and inhibition in 6-hydroxydopamine-lesioned rats

Previous single-unit recording studies have revealed that randomly selected pars reticulata neurons respond in a highly variable and complex fashion to intravenous administration of the dopamine agonist, apomorphine. The current studies were undertaken (1) to assess whether the variable pattern of responses of reticulata neurons to intravenous apomorphine correlates with their sites of projection and (2) to determine how reticulata responses to apomorphine might be altered by the presence of striatal dopaminergic supersensitivity. Extracellular, single-unit recording studies were conducted in anesthetized, paralyzed rats. Pars reticulata neurons were identified by antidromic activation from either the ventromedial nucleus of the thalamus or superior colliculus. Neurons of both subpopulations exhibited similar, highly variable changes in firing rate during the 10-min period immediately following intravenous injection of 320 micrograms/kg of apomorphine, a dose of the drug considered sufficient to stimulate striatal postsynaptic dopamine receptors. These responses, which were not qualitatively different from those previously observed among reticulata cells not distinguished on the basis of projection site, could be reversed by subsequent administration of dopamine antagonist drugs. In contrast to the variable responses in normal animals, the same dose of apomorphine caused a rapid and usually total inhibition of pars reticulata cell firing in rats which received 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway 6 to 8 weeks prior to recording experiments. These inhibitions of firing could also be reversed by administration of dopamine antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Single unit responses of substantia nigra pars reticula neurons to apomorphine: Effects of striatal lesions and anesthesia

Many of the behavioral consequences of dopamine system activation are thought to be mediated by substantia nigra pars reticulata output pathways. Extracellular, single unit recording studies were conducted to determine how i.v. administration of the dopamine agonist, apomorphine, affects the activity of these pars reticulata neurons. Results revealed that a 320 μg/kg dose of the drug, considered sufficient to stimulate striatal postsynaptic dopamine receptors, caused affinity variable changes in reticulata cell firing. Cells exhibited increases, decreases, or no changes in firing. Many cells also displayed marked minute to minute changes in firing. This non-uniform pattern of responses was not related to state of consciousness since similar responses were observed in both chloral hydrate-anesthetized as well as conscious, paralyzed rats. Both the increases and decreases could be reversed by subsequent administration of haloperidol. The variable responses to apomorphine were reduced but not totally prevented by striatal kainic acid lesions, suggesting that changes in striatonigral transmission may account for some but not all of the firing changes which were observed. A lower dose of apomorphine (20 μg/kg), thought to act primarily at dopamine cell autoreceptors, had little effect on reticula cell firing and did not modify the variable responses normally observed after the higher dose. These results contrast strikingly with the consistent excitatory responses to apomorphine which have previously been observed in the globus pallidus and suggest that complex or multiple indirect effects of the drug may contribute to the varied reticulata responses.

Effect of daily dose of chronic haloperidol and chronic apomorphine on behavioral hypersensitivity in the rat.

Behavioral hypersensitivity in the rat consisting of increased dopamine-mediated stereotypic behaviors has been found to follow a 10-day course of treatment with the neuroleptic haloperidol as well as with the direct dopamine agonist apomorphine. The daily dose versus response relationship for chronic haloperidol indicates that a threshold daily dose exists and that behaviors increase with increasing daily dose. On the other hand, low rather than high daily doses of chronic apomorphine induce behavioral hypersensitivity and the response decreases with increasing daily dose. Prolonged functional denervation of striatal postsynaptic dopamine receptors by either neuroleptic blockade or autoreceptor stimulation may explain these findings. The results may help elucidate the relative risk of daily neuroleptic dose on tardive dyskinesia development and indicate a possible mechanism for chronic agonist-associated side effects like L-Dopa dyskinesias.